A number of indole-dihydroindole alkaloids are currently either being marketed or are or have been on clinical trial as anticancer agents. These alkaloids include vincaleucoblastine (vinblastine, VLB)--marketed as VELBAN, U.S. Pat. No. 3,097,137; vincristine (VCR, leurocristine)--marketed as ONCOVIN, U.S. Pat. No. 3,205,220; vindesine (VDS)--marketed as ELDISINE, U.S. Pat. No. 4,191,688; vinzolidine, U.S. Pat. No. Re. 30,560; and vinepidine, U.S. Pat. No. 4,143,041. A large number of acid addition salts of these drugs are disclosed, including the naphthalene-1-sulfonate and the naphthalene-2-sulfonate.
In general, the sulfate salts of the above dimeric indole-dihydroindole alkaloids are favored during isolation, synthesis, formulation, etc. The drugs are customarily administered parenterally by the iv route and any pharmaceutically-acceptable soluble salt, such as the sulfate, which can provide the required concentration of drug, can be used. Sulfate salts of VLB and vincristine are prepared by neutralization of the base with dilute sulfuric acid (ethanol for example or other inert polar solvent may also be present to solubilize the base) followed by lyophilization. With these alkaloids, the lyophilized salt had adequate stability, but with vindesine, the lyophilized salt was not stable. Rolski, U.S. Pat. No. 4,259,242 addresses this problem and provides a method of preparing a stable monosulfate salt of vindesine by precipitation during neutralization of vindesine base with sulfuric acid in acetonitrile solution.
Vinzolidine is another indole-dihydroindole alkaloid whose sulfate salt has been found to be unstable. In contrast to the other alkaloids, vinzolidine is an orally active drug and must be capable of being provided in solid formulations such as capsules and tablets. While an injectable product like vindesine or vincristine can be lyophilized and the lyophilized product sealed in a dry, inert atmosphere, capsules and tablets are constantly exposed to air and water vapor.
Vinzolidine sulfate was prepared in eight different crystalline forms by employing different recrystallization solvents. While the stability of these forms varied considerably, none was found to be sufficiently stable to meet the stability requirements of an oral dosage form.
It is an object of this invention to prepare a vinzolidine salt which is sufficiently stable for use in oral dosage forms and which furnishes adequate vinzolidine blood levels on ingestion.